Preparation of provitamins



' esters and 7-dehydro sterols v invention also relates to novel Patented Feb. 20, 1945 Hans R.

E. I. du Pont Rosenberg, Wilmington, Del.,

de Nemours & Company,

assignor to Wil- . mington, Del., a corporation of Delaware No Drawing. I Application April 16, 1942,

. Serial No. 439,241

4 Claims.

This invention relates to the preparation of organic compounds containing a cyclo-pentanoperhydro-phenanthrene nucleus. More particularly it relates to the preparation of such com-. pounds from M-Z-hydroxy-steroid esters by the removal of acid groups preferred embodiments, it relates to the preparation of '7-dehydro from A -7-hydroxysterol monocarboxylic acid esters by the removal of monocarboxylic acid groups therefrom. The

procedural conditherefrom. In one of its sterol monocarboxylic acid is avoided. Another object is to provide new processes for making 7-dehydro steroids in which lowing description of the invention.

tions for preparing such 7-dehydro steroid compounds.

The thermal decomposition of diesters of 7- hydroxy-sterols and monocarboxylic acids, at reduced pressures has been described in U. S. P.

' 2,098,984. Under the conditions specified therein small yields of 'I-dehydro-sterol esters are formed. The '7-dehydro-sterol esters are then saponifled to remove the remaining acid groups.

7-dehydro-sterol esters may be prepared from such diesters of steroids by the procedure of U. S. P. 2,209,934 involving treatment with organic nitrogenous bases such as organic amines until an acid group has been removed. The '7-dehydro esters may then be reacted with a saponifying agent to yield '7.-dehydro sterols. The use of oxonium salt forming compounds in the place of all or part of such 'bases with or without additional assisting agents in addition has been described in U. S; P. 2,255,815.

While the above-described processes have com- -mercial utility certain of them have some shortcomings from the standpoint of a practical easily controllable process. The thermal decompositionat elevated temperatures and under reduced pressure require very careful supervision. The, maintenance of a high degree of vacuum inter.- poses economic and practical diiiiculties of operation. In addition, the heating of the ester melt causes decomposition of useful products into those of no economic value. Organic nitrogen bases and oxonium salt forming compounds have utility, but are somewhat expensive and are sometimes difficult to obtain.

An object of this invention is to provide new and useful processes for removing acid groups from organic esters containing a cyclo-pentanoperhydro-phenanthrene nucleus. A further object is to provide processes for making 7-dehydro steroid compounds which can be carried out'at moderate temperatures. A still further object is to provide processes for making 'I-dehydro sterol esters in which uneconomic lay-product formation medium with a substantial 56 the presence of ergosterol bands.-

It has now been found that acid groups can be removed from esterifled organic compounds containing a cyclopentano-perhydro-phenanthrene nucleus by heating them in the presence of an organic cyanic acid compound such as a nitrile Or an equivalent compound.

In a more limited sense the invention involves heating A- -I-hydroxy-steroid esters of monocarboxylic acids in a liquid medium in the presence of a substantial amount of an organic nitrile.

According to a more preferred aspect of the invention the above objects are accomplished by heating A -7-hydroxy steroid esters in a liquid proportion of a liquid nitrile until a material amount of acid groups The 7-dehydrosteroid further purified and/or of such steroid esters. compounds may then be processed.

In a preferred aspect of the invention a diester of a 7-hydroxy sterol and a monobasic organic carboxylic acid is heated to a temperature between C. and 300 C. with at least one half a molecular equivalent of a nitrile in a liquid medium for a period of at least one hour. In the event the nitrile chosenis a liquid at the temperature employed or can be liquefied by increased pressure, it is unnecessary to provide a further liquid medium.

The nitriles used in accordance with the teachlugs-hereof should not have a' deleterious action during the process. should be nondestructive of A -7-hydroxy steroid esters. In order to determine if the particular may be carried out:

Test for destructive properties Two milligrams of ergosterol or ergosterol acetate are heated in the presence of the nitrile or cyanate compound to be tested and heated in a sealed tube to a temperature of 200 C. for one hour. The reaction product is then diluted with ethyl alcohol and spectroscopically examined for The compound To be more specific they in question is suitable if the ergosterol is not destroyed. If desired, cyclohexane may be also used as a diluent in the test.

The invention will be further illustrated but is not intended to be limited by the following examples wherein the parts stated are parts by weight.

' Example 1 Example II Five parts of 7-hydroxy-cholesterol-dibenzoate were dissolved in thirty parts of phenyl-isothiocyanate and heated to reflux for two hours. The phcnyl-isothiocyanate was then distilled oil? under vacuum and acetone was added to the residue. Upon cooling, 0.52 part of 7-dehydrocholesterol-benzoate crystallizedout. This corresponds to a yield of 12% of theory.

It should be understood that the invention is.

not limited to the treatmentof the specific 7- hydroxy-sterol esters described in the working examples. On the contrary, it embraces the treatment of steroids generally wherein a double bond exists in a position adjacent to the esterifled hydroxy group in the 7-position regardless of whether additional substituents are also present in other positions in the molecule. Any ester compounds having the cycio-pentano-perhydrophenanthrene skeleton may be used wherein the ester group is in the 7-position and a double bond in the 5,6-position. Such substances are sometimes termed steroid or sterid compounds and include those having the nucleus referred to with or without side chains including said chains with other functional groups such as oxo, hydroxyl and carboxyl groups and their derivatives. Thus, the term "steroids" includes not only sterols, but also bile acids, plant heart poisons, saponin'es and sex hormones. Among the suitable polyesters of the above-described types are esters of '7-hydroxy-cholesterol, e. g., 7-hydroxy-cholesterol diacetate, 'l-hydroxy cholesterol di(nitrobenzoate) 7-hydroxy-sitosteryl diesters, e. g., 'l-hydroxy sitosterol dibenzoate, 7-hydroxy-sitosteroi di- (nitrobenzoate), etc.; 'l-hydroxy stigmasterol diesters, e. g., the dibenzoate, diacetate, etc.; 3,7- dihydroxy-5-cholenic acid 1 esters, A -androstentriol-'3,7,17-triesters, and the corresponding esters of pregnane series. esters include the simple or mixed carboxylic esters of 7-hydroxy sterol compounds obtainable from acids such as nitrobenzoic, m-dinitrobenzoic,

. chlorobenzoic, toluic, phenyl-acetic, cinnamic,

formic, acetic, propionic, butyric, valeric, etc. acids and their acid anhydrides and acid halides, e. g., acyl chlorides. Any of the diesters disclosed in U, S. Patents Nos. 2,209,923 and 2,215,727, for instance. may be used as starting materials in the present processes.

The amount of organic nitrile or cyanate can be varied over a fairly wide range. In general, it is advisable to have about an equimolar proportion of such compound based on the steroid Still other suitable treated present during the acid splitting reaction. From 1 to parts of nitrile or cyanate compound per part of steroid ester, for example, represents a practical range, and from 5 to 25 parts a preferred range. An excess of the nitrile or cyanate compound ingeneral renders the process more practical and results in higher yields The temperature and time may also be varied over'a fairly wide range, e. g., from C. and less to 300 C. and over. A temperature from C. to 260 C. represents a preferred range. The time may vary from' about 2 hours to 16 hours and over depending somewhat on the temperatures employed. For example, 2 hours heating at 220 C., 6 hours at 200 C., and 16 hours at 180 C. give substantially the same yields.

.It is not necessary, however, to convert all the diester to the '7-dehydro compound. The reaction may be cut short when partially complete.

In place of the specific nitriles set forth in the working examples may be substituted methyl cyanide, ethyl cyanide, cetyl cyanide, phenylacetic acid nitrile. Organic cyanic acid compounds'which are equivalents of nitriles can be used. These nitriles can be used with any of the steroid esters specifically mentioned or falling within the above definitions. Mixtures of two or more of such compounds can be used.

Similarly, in place of the particular cyanate compounds of the examples may be substituted benzyl isothiocyanate, cyclo-hexylisothiocyanata butyl-isothiocyanate, hemrl-isothiocyanate, phenyl-thiocyanate, benzyl-thiocyanate.

The new precedures hereof represent a distinct contribution to the art. The use of the nitriles for acid splitting of steroid esters to form 7-dehydro compounds is of special utility. The invention provides a new use for organic nitriles, isocyanates, thiocyanates, and is0thio cyanates. The compounds enable the acid splitting reaction to be carried out at lower temperatures with attendant advantages.

As many apparently Widely different emb0cllments of this invention may be made. without departing from the spirit and scope thereof, it is to be understood that the invention is not to be limited except as defined by the appended claims.

I claim:

l. The process which comprises heating the diester of a 7-hydroxy sterol and an organic monobasic carboxylic acid with a liquid organic nitrile selected from the class consisting of benzonitrile, methylcyanide, ethyl cyanide and phenylacetic acid nitrile, to a temperature between 100 C. and 300 C. for a period of at least one hour, and recovering therefrom a 7-dehydro sterol compound.

2. The process which comprises heating the diester of a 7-hydroxy sterol and an organic monobasic carboxylic acid with benzonitrile to a temperature between 100 C. and 300 C. for a period 01' at least one hour, andrecovering therefrom a 7 -dehydro sterol compound.

3. The process which comprises heating the diester of 7-hydroxy cholesterol and an organic monobasic carboxylic acid with benzonitrile to a temperature between 100 C. and 300 C. for a period of at least one hour, and recovering therefrom a 7-dehydro sterol compound.

4.'The process which comprises refluxin 7- hydroxy-cholesteroi-dibenzoate and benzonitriie in an atmosphere of nitrogen for a period or about 8 hours, and recovering therefrom a 7-dehydro sterol compound. i

Hans a. ROSENBERG. 

